Polymorphic form A of 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyric acid

ABSTRACT

A pharmaceutical composition, comprising: a compound of formula (1) in polymorphic crystalline Form A:  
                 
 
     together with a pharmaceutically acceptable carrier or excipient,  
     wherein the compound of formula (1) is present in polymorphic Form A (see, e.g., FIG.  6 ) substantially free of other polymorphic forms.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The polymorphic form A, as defined by powder x-ray diffraction,of4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyricacid has high solubility and bioavailability compared to othercrystalline forms.

[0003] 2. Description of the Background

[0004] Leukotrienes are metabolites of arachidonic acid through the5′-lipoxygenase pathway and are important mediators of allergicresponse, such as that involved in bronchial asthma. Drugs that exertantagonistic effects on the leukotrienes are useful for the treatment ofallergic diseases.

[0005] The synthesis and biological activity of manyphenoxyalkylcarboxylic acid derivatives, which are leukotrieneantagonists, are described by. Ohashi et al., U.S. Pat. No. 4,985,585.The compounds were obtained in laboratory scale amounts by silica-gelcolumn chromatography of the crude product mixtures. The solvent wasevaporated to give either a pale yellow oil or colorless crystals and nodeliberate effort was made to control crystal morphology.

[0006] We have observed that4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyricacid (1), which is Example 33 in Ohashi et al., is orally active fortreatment of asthma and allergic diseases and that the solid compoundcan crystallize into several distinct polymorphs when prepared in bulk.It has been discovered that the crystallization conditions, particularlytemperature, is critically important for preparing the differentpolymorphs.

[0007] We have also found that the solubility and the bioavailability ofone of these polymorphs, identified as orthorhombic crystals (Form V inTable 1, and Form A in FIG. 6), is superior to the other polymorphs andthus form A offers improved solid formulations.

SUMMARY OF THE INVENTION

[0008] The present invention provides a pharmaceutical compositioncomprising a compound of formula (1) in a selected crystalline form:

[0009] together with a pharmaceutically acceptable carrier or excipient,wherein the selected crystalline form is composed of polymorphic form A,substantially free of undesired polymorphs. By “substantially free” ismeant that little or no undesired polymorphs are detectable by powderX-ray diffractometry (PXRD). Typically, the polymorphic purity isgreater than 90% (defined by peak heights in the powder x-raydiffraction trace). Preferably, the desired crystalline form of theinvention is at least about 95% of the polymorphic form A (FIG. 6) asmeasured by relative peak heights in the region of 9° 2-theta.

[0010] The present invention also provides a process for obtaining formA of the compound of formula (1) in at least about 90% purity withrespect to other polymorphs. An exemplary crystallization processincludes the steps of dissolving compound (1) in 5 to 10 parts by weightof warm ethanol and 1-10 parts of water, agitating the resultingsuspension at 20-25° C. for 15-60 minutes and then cooling to 5-10° C.for an additional period of 1-4 hours, adding 5-15 parts of water,agitating the mixture at 5-10° C. for an additional 1-4 hours, andisolating crystals of compound (1) containing at least about 90% byweight of form A (FIG. 6).

[0011] Accordingly, a pharmaceutical composition is provided, whichcomprises a compound of formula (1) in solid form:

[0012] together with a pharmaceutically acceptable carrier or excipient,

[0013] provided that the compound of formula (1) is present inpolymorphic Form A and is substantially free of other polymorphic forms.In a preferred embodiment of the invention, the compound of formula (1)is present as orthorhombic crystals. Also the invention can be made intothe form of a tablet or capsule. Preferably, the composition of theinvention gives rise to a PXRD pattern substantially as shown forpolymorphic Form A in FIG. 6. Moreover, it is preferably that at leastabout 90% of the compound of formula (1) is polymorphic Form A, asdefined by PXRD peak heights around 9° 2-theta. The composition mayfurther comprise lactose and microcrystalline cellulose. The tablet canhave different weights, for example, between about 250 and about 500 mg.

[0014] The present invention is also directed to a compositioncomprising isolated crystals of the compound of formula (1)

[0015] in which the isolated crystals of compound (1) are present inpolymorphic Form A and substantially free of other polymorphs. In apreferred embodiment the isolated crystals of compound (1) are presentas orthorhombic crystals. The isolated crystals of compound (1) of thepresent invention preferably exhibit a PXRD pattern substantially asshown for polymorphic Form A in FIG. 6. More preferably, the isolatedcrystals of the invention are at least about 90% polymorphic Form A, asdefined by PXRD peak heights around 9° 2-theta. The invention alsoprovides a composition having isolated crystals of compound (1), whichcomposition contains at least about 90% of polymorphic Form A withrespect to other polymorphic forms.

BRIEF DESCRIPTION OF THE FIGURES

[0016]FIG. 1 Powder X-ray Diffraction Pattern and DSC Chart of Form I

[0017]FIG. 1a DSC Chart of Form I

[0018]FIG. 2 Powder X-ray Diffraction Pattern and DSC Chart of Form II

[0019]FIG. 3 Powder X-ray Diffraction Pattern and DSC Chart of Form III

[0020]FIG. 4 Powder X-ray Diffraction Pattern and DSC Chart of Form IV

[0021]FIG. 5 Powder X-ray Diffraction Pattern and DSC Chart of Form V

[0022]FIG. 6 X-ray diffraction patterns of three polymorphs.

[0023]FIG. 7. Schematic process for dry granulation

[0024]FIG. 8. Schematic process for wet granulation

DETAILED DESCRIPTION OF THE INVENTION

[0025] Ester (4) can be synthesized by reacting a phenol of formula (2):

[0026] wherein R is an acid protecting group, such as methyl or ethyl,with the bromo compound of formula (3):

[0027] in an organic solvent, for example acetone, methylethylketone,diethylketone or dimethylformamide. The reaction may be conducted frombelow room temperature up to the reflux temperature of the solvent, inthe presence of an inorganic base, e.g., potassium carbonate or sodiumcarbonate. The addition of potassium iodide is also recommended.Analogues of compound (3) having alternative leaving groups, such aschloro and tosylate, may be used to effect the coupling reaction.

[0028] Removal of the acid protecting group by alkaline ester hydrolysisand extractive work-up gives compound (1) as a white solid.

[0029] Recrystallization of the white solid to give essentially pureform A crystals (FIG. 6), (e.g., 90% or more,. preferably at least 95%)can be accomplished by dissolving compound (1) in 5 to 10 parts byweight of ethanol at 25-40° C. to give a yellow to orange solution. Theethanol solution is charged with 1-10 parts of water and agitated at20-25° C. for about 15-60 minutes and then at 5-10° C. for an additionalperiod of 1-4 hours, preferably 2.0-3.0 hours, resulting in an off-whitesuspension.

[0030] To, this suspension is added 5-15 parts of water and the mixtureis agitated at 5-10° C. for an additional 1-4 hours, preferably 1.5-2.0hours. A solid, white to off-white product is isolated by vacuumfiltration and the filter cake is washed with water and dried in avacuum at 25-40° C. for 12-24 hours.

[0031] Other recrystallization conditions are also able to produce formA, such as dissolving compound (1) in a lower alcohol (isopropanol), andcooling the solution form crystals.

[0032] Therapeutic Formulations

[0033] Pharmaceutical compositions containing the orthorhombic form ofcompound (1) may be formulated for oral administration with inertexcipients, such as a starch binder excipient, alone or in combinationwith microcrystalline cellulose and a suitable lubricant. Other suitableexcipients include polyvinylpyrrolidinone, gelatin, hydroxy cellulose,acacia, polyethylene glycol, mannitol, sodium chloride, sodium citrateor any other excipient known to those of skill in the art ofpharmaceutical compositions.

[0034] Excipients in tablets are generally classified according to theirfunction, such as diluents (also called bulking agents and fillers),binders which hold the ingredients together in the compressed tablet,disintegrants which help facilitate the break-up of the tablet whenplaced in a fluid environment to release the active ingredient, andlubricants to improve the release of the compressed tablet from the dieand punches. In addition, tablets may contain other substances intendedto improve the tabletting process, such as flow additives, flavors,sweeteners and anti-oxidants

[0035] Tabletting and some capsule filling operations are based on theability of certain powders to bind under compression. Compressed tabletsmay be prepared by wet granulation, dry granulation, or directcompression. The wet granulation process includes mixing the componentsin powder form, preparing the granulating binder solution, thoroughlymixing the components with the granulating binder solution to form adough, coarse screening the mass through a sieve, drying, grinding,adding the lubricant and compressing the tablets from the resultingmixture.

[0036] A preferred tablet formulation is a wet granulation containingpolymorphic form A of compound (1) lactose regular, microcrystallinecellulose 101, crosscarmellose, magnesium stearate and purified water,coated with Opadry II white. The tablets should weigh from 100 mg to1000 mg, preferably 250 mg to 500 mg.

[0037] Dry granulation involves the steps of mixing the powdercomponents, compressing the mixture into hard slugs, grinding the slugsinto desired particle size, screening, adding other excipients ifnecessary, and compressing the mixture into tablets. The most economicaltabletting method, direct compression, requires only two steps, mixingthe dry components and compressing the mixture into tablets.

[0038] Suitable direct compression binders include microcrystallinecellulose, compressible sugars, certain calcium salts, lactose anddextrose. Of these, microcrystalline cellulose is preferred. Thatexcipient also displays good disintegration properties. Other goodbinders include calcium phosphates and compressible sugars. Calcium saltbinders generally require the use of disintegrants. Mannitol andsorbitol have certain taste advantages, but they lack binding propertiesand require a disintegrant.

[0039] The tablets typically exhibit a tablet hardness of greater than 2kilopond (kp)/cm.sup.2, more preferably a tablet hardness of greaterthan 5, most preferably about 10 to about 20 kp/cm.sup.2 and adisintegration time of less than 30 minutes, more preferably less than15 minutes as measured utilizing the standard USP disintegration test inwater.

[0040] The polymorphic form A of compound (1) may also be formulated incapsules. Solid carriers include starch, lactose, calcium sulfate,di-hydrate, teffa alba, magnesium stearate or stearic acid, talc,pectin, acacia, agar or gelatin. The carrier may also include asustained release material such as glycerol monostearate or glyceroldistearate, alone or with a wax. The amount of solid carrier varies but,preferably, will be between about 20 mg to about 1 gram per dosage unit.

[0041] Encapsulation can be done in any suitable manner, typically byuse of a polymer coating used for microencapsulation, enteric coatings,multiple coatings, and the like. The polymer coating may resistdisintegration upon contact with the saliva but instantly release thecompound upon contact with gastric juice in the stomach, in order tocontrol the taste of the composition. Alternatively, the polymer coatingmay be one that resists rapid disintegration in the presence of gastricjuice. Suitable coating polymers include biodegradable polymers such aspolylactic acid, polygycolic acid, copolymers of lactic and glycolicacid, polyorthoesters, and polyanhydrides thereof. The compound also canbe encapsulated by a polymer coating such as a polysaccharide (e.g.,methyl or ethyl cellulose) or within a liposomal delivery system.Suitable methods of preparing compositions containing microencapsulatedactive ingredients are described, for example, in U.S. Pat. Nos.4,462,982, 4,710,384, 5,178,878, and 5,709,886. Preferably, themicroencapsulated compounds have a mean particle size of about 50microns to about 120 microns (e.g., about 70 microns to about 100microns).

[0042] Typical doses of compound (1) in tablets and capsules are fromabout 1.0 mg/kg to about 100 mg/kg. Administration intervals vary withthe patient's age, weight and general condition. In general, the drug isadminister from one to four times daily.

EXAMPLES

[0043] In general, tablets are formed utilizing a carrier such asmodified starch, alone or in combination with 10% by weight ofcarboxymethyl cellulose (Avicel). The formulations are compressed atfrom 1,000 to 3,000 pounds pressure in the tablet-forming process. Thetablets preferably exhibit an average hardness of about 1.5 to 8.0kp/cm.sup.2, preferably 5.0 to 7.5 kp/cm2. Disintegration time variesfrom about 30 seconds to about 15 or 20 minutes. The following examplesgive specific embodiments of the invention but should not be construedas limiting its scope.

EXAMPLE 1

[0044] Synthesis of ethyl4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)-propoxy]-2-propylphenoxy]butyrate

[0045] To a stirred mixture of ethyl4-(6-acetyl-3-hydroxy-2-propylphenoxy)butyrate (1.6 g), potassium iodide(0.5 g) and potassium carbonate (1.45 g) in acetone (30 ml) was addeddrop wise a solution of4-(3-bromopropylthio)-2-hydroxy-3-propylphenyl-ethanone (1.9 g) inacetone (10 ml) with heating to reflux. After refluxing six hours themixture was cooled to room temperature and inorganic materials wereseparated by filtration. The filtrate was concentrated and the residuewas separated and purified by silica-gel column chromatography (elutingwith benzene:ethyl acetate=9:1) to give the title compound as crudecrystals (2.1 g, 72.4%) which were recrystallized from ethanol to givecolorless crystals, mp 65-66° C.

EXAMPLE 2

[0046] Synthesis of4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyricacid

[0047] To a mixture of ethyl 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyrate (2.1 g) in ethanol(10 ml) was added a solution of sodium hydroxide (0.26 g) dissolved intowater (10 ml). After heating on a hot water bath for 5 minutes, themixture was cooled by adding ice-water and was made acidic by additionof hydrochloric acid, followed by extraction with ethyl acetate. Theorganic layer was washed with water, dried over sodium sulfate andconcentrated. The resultant residue was separated and purified bysilica-gel column chromatography (eluting with ethanol:methylenechloride=3:100) to give the title compound (1.3 g, 65.2%) as colorlesscrystals, mp 79-81° C.

EXAMPLE 3

[0048] Crystalline polymorphism

[0049] After re-crystallization with individual solvents, compound (1)was subjected to powder X-ray diffractometry, thermal analysis anddetermination of solubility in ether; thus an exploratory evaluation ofthe crystalline polymorphism was made. The results demonstrate thatcompound (1) is present in 5 different crystalline polymorphs.

[0050]FIGS. 1-5 show the powder X-ray diffraction patterns and DSC formetastable crystal types I through V. Table 1 shows the preparatoryprocedures for types I through V and their solubility in ether. TABLE 1Preparation of Crystalline Polymorphs and Their Solubilities in EtherCrystal Solubility form Preparatory procedures (mg/mL) I After compound(1) was heated and dissolved in a 4-fold quantity 36.7 of isopropylether, the resultant solution was allowed to cool at room temperature(crystallization took place in the vicinity of 40° C.). Alternatively,after the compound was heated and dissolved in a 5-fold quantity ofacetonitrile, the resultant solution was maintained at 40° C. in anincubator. II After compound (1) was heated and dissolved in a 10-foldquantity 40.5 of acetonitrile, the resultant solution was cooled andagitated in an ice water bath. III After compound (1) was heated anddissolved in a 10-fold quantity 35.3 of acetonitrile, the resultantsolution was maintained at 25° C. in an incubator. IV After compound (1)was heated and dissolved in a 5-fold quantity 45.8 of ethanol, a2.5-fold quantity of water was added thereto while hot, which was thenallowed to cool at room temperature. V After compound (1) was heated anddissolved in a 5-fold quantity 47.6 of ethanol, the resultant was cooledand agitated in an ice water bath, and a 2.5-fold quantity of water wasadded thereto while cold. Alternatively, compound (1) was heated anddissolved in a 3.5-fold quantity of isopropanol and the resultingsolution was maintained at 0° C. in a refrigerator.

[0051] Table 1 shows that the crystallization temperature was criticallyimportant in preparing the various crystalline polymorphs. When the bulkingredient is prepared, crystallization takes place on a large scale andfailure in controlling the exact temperature can result in a mixture ofstable and metastable crystals, giving a larger variance in thephysicochemical properties and bioavailability among production lots,against which precautions should be taken.

EXAMPLE 4

[0052] Bulk crystallization procedure for obtaining orthorhombicpolymorph, crystal type V (Form A).

[0053] Off-white solid compound (1) 34 g was dissolved in 204 mL (6parts wrt mass of dry filter cake) of ethanol (40° C.) giving a yellowto orange solution. With moderate agitation, the ethanol solution wascharged with 43 mL (1.3 parts) of water. The reaction mixture was cooledto 20-25° C. and agitated at 20-25° C. for about 15 minutes and then at10-15° C. for an additional period of 1-2 hours, appearing as anoff-white suspension.

[0054] To the resulting suspension was then charged 364 mL (10.7 parts)of water and the mixture was agitated at 5-10° C. for an additional 1-2hours. A solid, white to off-white product was isolated by vacuumfiltration. The filter cake was washed with 2×30 mL of water. The offwhite solid was dried in a vacuum at 35-40° C. for 24 hours.

EXAMPLE 5

[0055] Solubility data of compound (1) in ethanol/water (2:1) desiredundesired polymorphic form monoclinic temperature V (form A) polymorph22° C.  6.7 g/L 3.4 g/L 30° C. 15.7 g/L 6.1 g/L 40° C.   46 g/L 17.2g/L 

[0056] Samples of compound (1) (5 g) were suspended in ethanol/water(2:1, 100 mL) and stirred for one hour at temperatures of 22° C., 30°C., and 40° C., respectively. The suspensions were filtered and thesolids dried in a vacuum oven at room temperature overnight to give theinsoluble material. The solubilities were calculated by subtractivemeans based on recovered material.

EXAMPLE 6

[0057] In general wet granulation tablets were prepared with a bindingsolution comprised of an aqueous solution of hydroxypropylcellulose.Granulation was performed with a high shear granulator, the resultantwet mass was fluid bed dried, milled, blended with extragranularexcipients to aid disintegration, flow and compressibility, andsubsequently tabletted on a tablet press. These core tablets were filmcoated to standardize appearance and to improve compliance (i.e. ease ofswallowing). Excipients included, but were not limited to croscarmellosesodium, magnesium stearate, hydroxypropylcelluse,hydroxypropylmethylcellulose, lactose, glyceryl behenate,polyvinylpyrrolidine, mannitol,titanium dioxide and microcrystallinecellulose.

EXAMPLE 7

[0058] In general, the dry granulation formulation was formed by dryblending (in a tumble blender or high shear mixer) a portion of thebinding, disintegration and lubrication powders. This dry powder blendwas formed into granules through the use of a roller compactor equippedwith an oscillating (shear) granulator. The ss mesh screen, gap width,gap force, roller speed and granulator speeds were defined to optimizethe formulation physical parameters as apparent to those skilled in theart of pharmaceutical processing. Excipients included, but were notlimited to croscarmellose sodium, magnesium stearate,hydroxypropylcelluse, hydroxypropylmethylcellulose, lactose, glycerylbehenate, polyvinylpyrrolidine, mannitol,titanium dioxide andmicrocrystalline cellulose.

EXAMPLE 8

[0059] Specific formulation for dry granulation. TABLE 3.4.1 Proposedinitial formulation compositions for dry granulation prototypingPrototype 1 Prototype 2 No. Ingredient (mg/tablet) (mg/tablet) 1Compound (1), Type V (Form A) 250 250 2 Lactose regular/fast flow 7.5 —3 Microcrystalline cellulose PH101 31 31 4 Croscarmellose sodium 20 20 5Hydroxypropylcellulose 80 — 6 Magnesium stearate 2.0 — 7Hydroxypropylmethylcellulose 2910 8.0 — 8 Titanium Dioxide 1.0 — 9Carnauba wax 0.5 0.5 10 Polyvinylpyrrolidone — 85 11 Mannitol — 3.5 12Glyceryl behenate — 2.0 13 Opadry II (white) — 8.0 Total 400 mg 400 mg

EXAMPLE 9

[0060] Specific formulations for wet granulation. TABLE 3.4.2 Proposedinitial formulation compositions for wet granulation prototypingPrototype 3 Prototype 4 No. Ingredient (mg/tablet) (mg/tablet) 1Compound (1), Type V (Form A) 250 250 2 Lactose regular/fast flow 7.5 —3 Microcrystalline cellulose PH101 32 32 4 Croscarmellose sodium 25 25 5Hydroxypropylcellulose 25 — 6 Magnesium stearate 2.0 — 7Hydroxypropylmethylcellulose 2910 7.0 — 8 Titanium Dioxide 1.0 — 9Carnauba wax 0.5 0.5 10 Polyvinylpyrrolidone — 30 11 Mannitol — 3.5 12Glyceryl behenate — 2.0 13 Opadry II (white) — 7.0 Total 350 mg 350 mg

[0061] The wet granulation process is given in the chart in FIG. 8.

[0062] The preferred embodiments of the invention have been describedabove in detail. Various modifications and improvements thereto willbecome readily apparent to those skilled in the art. The foregoingexamples are intended to be non-limiting and exemplary of the inventiondescribed in the foregoing specification and claimed below.

EXAMPLE 10—PXRD Analysis

[0063] The samples were prepared by a normal front packing technique andrun on a Siemens D5000 Diffractometer System. A high-resolutionCu-Kα-source was used, operating at 50 kV/35 mA. The secondary beam wasmonochromatized by a Kevex solid state detector. The step scan mode wasused for data collection within the range of 2.5°-35° (2-theta). Theobtained data were processed by Diffrac Plus™ Software.

[0064] The parts of the diffraction patterns of three differentpolymorphs are shown in FIG. 6, determined as Form A (likely anorthorhombic structure, specified type V), Form B (I) and Form C (II)(both monoclinic lattices) are also shown.

[0065] As on can see the top pattern is quite different from the othertwo. The differences are clearly marked with arrows above the top trace.Most of the single peaks on the upper pattern became doublets on theother two. This strongly suggests a structural transition with loweringof the overall symmetry. In order to find out some criteria for betterdistinguishing of these polymorphous, an attempt for indexing theunknown lattices was performed. The results reveal an orthorhombiclattice (top trace, Form A) and a monoclinic one (middle trace, Form B).The bottom trace (Form C) has also a monoclinic lattice very similar tothat one of Form B, but with some missing reflections (marked witharrows) that could result from some structural differences.

[0066] The structure of our Form A is very close to Form V in Table 1and FIG. 5, although there are some differences at the range 19-25°2-theta. On the other hand, the diffraction patterns for polymorphousForm I and Form II match well with Forms B and C, as they all apparentlyshow the splitting of the main reflections due to reducing the overallsymmetry from orthorhombic to monoclinic.

[0067] Because crystallographic characterizations of all fivepolymorphous described in Table 1 are difficult to reproduce, we willcharacterize the structural state of compound (1) in pharmaceuticalsamples only by means of its appearance as Form A, as defined by PXRD.

1. A pharmaceutical composition, comprising: a compound of formula (1)in solid form:

together with a pharmaceutically acceptable carrier or excipient,provided that the compound of formula (1) is present in polymorphic formA and is substantially free of other polymorphic forms.
 2. Thecomposition of claim 1 in which the compound of formula (1) is presentas orthorhombic crystals.
 3. The composition of claim 1, which is in theform of a tablet or capsule.
 4. The tablet or capsule of claim 3, whichgives rise to a PXRD pattern substantially as shown for polymorphic FormA in FIG.
 6. 5. The composition of claim 1, wherein at least about 90%of the compound of formula (1) is polymorphic Form A, as defined by PXRDpeak heights around 9° 2-theta.
 6. The composition of claim 1, furthercomprising lactose and microcrystalline cellulose.
 7. The tablet ofclaim 3, which weighs between 250 and 500 mg.
 8. A compositioncomprising isolated crystals of the compound of formula (1)

in which the isolated crystals of compound (1) are present inpolymorphic Form A and substantially free of other polymorphs.
 9. Thecomposition of claim 8, wherein the isolated crystals of compound (1)are present as orthorhombic crystals.
 10. The composition of claim 8,wherein the isolated crystals of compound (1) exhibit a PXRD patternsubstantially as shown for polymorphic Form A in FIG.
 6. 11. Thecomposition of claim 8, wherein the isolated crystals are at least about90% polymorphic Form A, as defined by PXRD peak heights around 9°2-theta.
 12. The composition of claim 8, wherein the isolated crystalsof compound (1) contain at least about 90% of polymorphic Form A withrespect to other polymorphic forms.